1. Field of the Invention
The present invention relates to analogs of haloperidol possessing anti-psychotic properties and clozapine-like therapeutic profiles.
2. Description of the Prior Art
Schizophrenia is a chronic disease that is characterized by positive (hallucinations, delusions), negative (social withdrawal, flattened affect) and cognitive (formal thought disorder, executive memory dysfunction) symptoms. The dopamine hypothesis, that schizophrenia stems from excessive midbrain dopamine transmission, originated from studies with neuroleptics that revealed correlations between clinical efficacy, effects on dopamine metabolism (Carlsson & Lindqvist, Acta Pharmacol. Toxicol. 20:140-144, 1967) and binding to dopamine receptors (Creese et al., Science 192:481-482, 1976). In addition, drugs that increase synaptic dopamine concentration, (e.g., amphetamines) produce aberrant, stereotyped behavior in animals (W T McKinney, in S C Shultz and C A Tamminga (eds) Schizophrenia: Scientific Progress. Oxford University Press, New York, pp 141-154, 1989) and schizophrenia-like symptoms in humans (Snyder, Am. J. Psychol. 130:61-67, 1976).
The therapeutic treatment of schizophrenic patients, as well as patients suffering from other psychoses, by the administration of neuroleptic drugs. One class of such drugs comprises the so-called typical antipsychotic agents (TAAs), such as chlorpromazine [2-chloro-N,N-dimethyl-10H-phenothiazine-10-propanamine, described in U.S. Pat. No. 2,645,640], haloperidol [4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]-1-(4-fluorophenyl)-1-butanone, described in U.S. Pat. No. 3,438,991], sulpiride [5-aminosulfonyl)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2-methoxybenzamide, described in U.S. Pat. No. 3,334,826], and chemically closely related compounds, is widespread. Haloperidol is a drug of choice in the treatment of schizophrenia and acts in part by inhibiting dopamine receptors in the CNS [Seeman, P.; Lee, T.; Chau-Wong, M.; Wong, K Nature, (1976), 261, 717]. While control of schizophrenic symptoms has been successful, treatment with these drugs does not cure the psychotic patient, who will almost certainly relapse if medication is discontinued.
Moreover, some of the known neuroleptics produce unwanted side effects. For example, the side effects of many antipsychotic drugs such as haloperidol, for example, include the so-called extrapyramidal symptoms (EPS), such as rigidity and tremor, continuous restless walking, akathisia, dystonia, late dyskinesia and tardive dyskinesia (TD), e.g., Parkinsonism dyskinesia, which causes facial grimacing, and involuntary movements of the face and extremities. The occurrence of orthostatic hypotension in patients taking anti-psychotic drugs is also common. These side effects are believed to be caused by blockage of the dopaminergic neurotransmission by the administered neuroleptics [Rowley, M.; Bristow, L. J.; Hutson, P. H. J Med. Chem. 2001, 44 (4), 477; Jaber, M.; Robinson, S. W.; Missale, C.; Caron, M. G. Neuropharm. 1996, 35 (11), 1503; Capuano, B.; Crosby, I. T.; Lloyd, E. J. Curr. Med. Chem. 2002, 9, 521.
The incidence rate of TD increases throughout the patient's exposure to antipsychotic drugs. The longer the exposure, the higher the patient's risk of developing, e.g., TD. This phenomenon points to the inadequacy of preclinical trials which only assess the risk of TD during the trial period. This phenomenon also suggests that the neuronal insults associated with TD are cumulative and the process which leads to this disease may be insidious and subtle in nature.
Anticholinergic agents such as Cogentin.RTM., have been used to reduce the Parkinson-like side effects, but these also cause their own side effects such as mental and/or physical impairment, tachycardia, dysuria and gastrointestinal symptoms.
Recently, atypical antipsychotic agents (AAAs), such as clozapine [8-chloro-1-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e]-[1,4]-diazepine, described in U.S. Pat. No. 3,539,573] and olanzapine [2-Methyl-10-(4-methyl-1-piperazinyl)-4H-thieno-[2,3-b][1,5]benzodiazepine, described in U.S. Pat. No. 5,229,382], have been introduced, which possess a therapeutic profile exhibiting greatly reduced Parkinson-like side effects. However, the TAAs also possess unwanted side effects as well, e.g., hypotension, sedation, confusion, weight gain, inter alia. Therefore, large numbers of patients continue to receive the TAAs such as, e.g., haloperidol.
Thus, there exists a continuing need in the art for antipsychotic drugs for the treatment of psychoses that produce fewer or less severe manifestations of the above discussed common side effects. In addition, because of the frequent long term administration of neuroleptics and the problems with patient compliance, there is a further need in the art for long lasting neuroleptics, which can be formulated into sustained release depot preparations, without causing the side effects mentioned above.